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Effects of Acid and Lactone Forms of Eight HMG-CoA Reductase Inhibitors on CYP-Mediated Metabolism and MDR1-Mediated Transport

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Purpose

With the growing clinical usage of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), the number of reports concerning serious drug–drug interaction has been increasing. Because recent studies have shown that conversion between acid and lactone forms occurs in the body, drug–drug interaction should be considered on both acid and lactone forms. Thus, we investigated the inhibitory effects of acid and lactone forms of eight statins, including one recently withdrawn, cerivastatin, and two recently developed, pitavastatin and rosuvastatin, on cytochrome P450 (CYP) 2C8, CYP2C9, and CYP3A4/5 metabolic activities and multidrug resistance protein 1 (MDR1) transporting activity.

Methods

The inhibitory effects of statins on CYP metabolic activities and MDR1 transporting activity were investigated using human liver microsomes and MDR1-overexpressing LLC-GA5-COL150 cells, respectively.

Results

The acid forms had minimal inhibitory effects on all CYP activities tested, except for fluvastatin on CYP2C9-mediated tolbutamide 4-hydroxylation (IC50 = 1.7 μM) and simvastatin on CYP3A4/5-mediated paclitaxel 3-hydroxylation (12.0 μM). Lactone forms showed no or minimal inhibitory effects on CYP2C8, CYP2C9, and CYP2C19 activities, except for rosuvastatin on the CYP2C9 activity (20.5 μM), whereas they showed stronger inhibitory effects on the CYP3A4/5 activity with the rank order of atorvastatin (5.6 μM), cerivastatin (8.1 μM), fluvastatin (14.9 μM), simvastatin (15.2 μM), rosuvastatin (20.7 μM), and lovastatin (24.1 μM). Pitavastatin and pravastatin had little inhibitory effect, and a similar order was found also for testosterone 6β-hydroxylation. MDR1-mediated transport of [3H]digoxin was inhibited only by lactone forms, and the rank order correlated with that of inhibitory effects on both CYP3A4/5 activities. Inhibitory effects on MDR1 activity, and on both CYP3A4/5 activities, could be explained by the lipophilicity; however, a significant correlation was found between the lipophilicity and inhibitory effects on CYP2C8-mediated paclitaxel 6α-hydroxylation.

Conclusions

We showed the difference between the acid and lactone forms in terms of drug interaction. The lipophilicity could be one of the important factors for inhibitory effects. In the case of statins, it is important to examine the effects of both forms to understand the events found in clinical settings, including the pleiotropic effects.

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Authors and Affiliations

  1. Department of Hospital Pharmacy, School of Medicine, Kobe University, 7-5-2, Kusunoki-Cho, Chuo-Ku, Kobe, 650-0017, Japan

    Toshiyuki Sakaeda, Chiho Komoto, Mikio Kakumoto, Jiang-shu Jin, Koichi Iwaki, Kohshi Nishiguchi, Tsutomu Nakamura & Katsuhiko Okumura

  2. Tokyo New Drug Research Laboratories I, Kowa Company, Ltd., Higashimurayama, 189-0022, Japan

    Hideki Fujino

  3. Department of Clinical Evaluation of Pharmacotherapy, Kobe University Graduate School of Medicine, Kobe, 650-0047, Japan

    Noboru Okamura & Katsuhiko Okumura

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  1. Toshiyuki Sakaeda
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  2. Hideki Fujino
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Correspondence to Toshiyuki Sakaeda.

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Sakaeda, T., Fujino, H., Komoto, C. et al. Effects of Acid and Lactone Forms of Eight HMG-CoA Reductase Inhibitors on CYP-Mediated Metabolism and MDR1-Mediated Transport. Pharm Res 23, 506–512 (2006). https://doi.org/10.1007/s11095-005-9371-5

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